Fibroblast Growth Factor 19-A Novel Prognostic Biomarker And Therapeutic Target For Sepsis

Part Ⅰ High level of serum FGF19 at ICU admission is associated with 28-day mortality in sepsis patientsAim:Explore the value of the baseline level of fibroblast growth factor 19(FGF19)in predicting 28-day mortality from sepsis.Methods:A total of 220 consecutive adult patients with sepsis who were admitted to our intensive care unit(ICU)during 2020 were prospectively recruited.Patients were categorized as survivors or non-survivors according to status at 28 days.Levels of FGF19 and other parameters were measured during 24 hours after the diagnosis of sepsis.Receiver operating characteristic(ROC)analysis was used to determine the optimal cutoff of FGF19 in prediction of survival.Prognostic factors were identified using Cox regression analysis.Results:The serum FGF19 level was much higher in non-survivors than in survivors(355.0 pg/mL[range:37.2,2315.6]vs.127.3 pg/mL[5.7,944.1];P<0.05).ROC analysis indicated an FGF19 level of 180 pg/mL was the optimal cutoff value and it had a better predictive value than PCT or CRP.Multivariable Cox regression analysis showed that FGF19 level and the change in sequential organ failure assessment(ΔSOFA)score at baseline were independently and significantly associated with 28-day mortality.ΔSOFA and FGF19 together had a significantly better predictive value than ΔSOFA alone.Conclusion:Sepsis patients with high serum levels of FGF19 at ICU admission were associated with an increased risk of 28-day mortality in our ICU.Part Ⅱ FGF15 Protects Septic Mice by Inhibiting Inflammation and Modulating Treg ResponsesAim:The current study aimed at investigating whether FGF15 could inhibit inflammation and modulate compensative regulatory T cell(Treg)in sepsis mouse.Methods:A total of 54 male C57BL/6 mice were randomized divided into three groups:sham,cecal ligation and puncture(CLP),and CLP+FGF15.Following the sham or CLP procedure,male CLP C57BL/6 mice were intravenously injected with vehicle saline or FGF15 beginning at 2 h post the procedure every 12 h for three days.Twenty-seven mice were euthanized and their serum and liver samples were collected for examination of cytokines and Tregs by enzyme-linked immunosorbent assay(ELISA),Western blot and flow cytometry.The remaining mice were monitored for their survival up to 14 days post procedure.Moreover,the purified hepatic CD4+T cells were co-cultured in transwell plates with unmanipulated NCTC 1469 cells or the cells that had been transfected with the control or fibroblast growth factor receptor 4(FGFR4)-specific siRNA and treated with,or without,Lipopolysaccharides(LPS)for 24 h,followed by treatment with vehicle PBS or FGF15 for 48 h.Cells or supernatant were collected for examination of cytokines and Tregs by enzyme-linked immunosorbent assay(ELISA),Western blot and flow cytometry.Results:Compared with the CLP group of mice,treatment with FGF15 significantly prolonged the mean survival days of mice,mitigated hepatic inflammation and reduced the frequency of apoptotic cells in the liver of mice.FGF15 treatment decreased the percentages of hepatic Tregs,hepatic interleukin 2(IL-2),transform growth factor β(TGF-β)and forkhead box protein 3(FOXP3)expression in septic mice,accompanied by decreasing serum IL-1β,tumor necrosis factor-alpha(TNF-α),IL-6 and IL-10 levels.Similarly,FGF15 treatment also attenuated the LPS-increased frequency of Tregs,FOXP3 and IL-2 expression and IL-1β,TNF-α,IL-6 and IL-10 secretion in vitro after co-culture with NCTC 1469 cells,but not co-cultured FGFR4-silenced NCTC 1649 cells.Conclusion:FGF15 treatment through FGFR4 ameliorated hepatic inflammation and its compensative Treg responses,which were associated with protecting from septic death in mice.